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PMID:15133037

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Citation

Kolli, S, Zito, CI, Mossink, MH, Wiemer, EA and Bennett, AM (2004) The major vault protein is a novel substrate for the tyrosine phosphatase SHP-2 and scaffold protein in epidermal growth factor signaling. J. Biol. Chem. 279:29374-85

Abstract

The catalytic activity of the Src homology 2 (SH2) domain-containing tyrosine phosphatase, SHP-2, is required for virtually all of its signaling effects. Elucidating the molecular mechanisms of SHP-2 signaling, therefore, rests upon the identification of its target substrates. In this report, we have used SHP-2 substrate-trapping mutants to identify the major vault protein (MVP) as a putative SHP-2 substrate. MVP is the predominant component of vaults that are cytoplasmic ribonucleoprotein complexes of unknown function. We show that MVP is dephosphorylated by SHP-2 in vitro and it forms an enzyme-substrate complex with SHP-2 in vivo. In response to epidermal growth factor (EGF), SHP-2 associates via its SH2 domains with tyrosyl-phosphorylated MVP. MVP also interacts with the activated form of the extracellular-regulated kinases (Erks) in response to EGF and a constitutive complex between tyrosyl-phosphorylated MVP, SHP-2, and the Erks was detected in MCF-7 breast cancer cells. Using MVP-deficient fibroblasts, we demonstrate that MVP cooperates with Ras for optimal EGF-induced Elk-1 activation and is required for cell survival. We propose that MVP functions as a novel scaffold protein for both SHP-2 and Erk. The regulation of MVP tyrosyl phosphorylation by SHP-2 may play an important role in cell survival signaling.

Links

PubMed Online version:10.1074/jbc.M313955200

Keywords

Amino Acid Sequence; Animals; Cell Line, Tumor; Cell Survival; Cells, Cultured; Culture Media, Serum-Free; DNA-Binding Proteins; Enzyme Activation; Epidermal Growth Factor/metabolism; Fibroblasts/cytology; Fibroblasts/metabolism; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mitogen-Activated Protein Kinases/metabolism; Molecular Sequence Data; Phosphorylation; Protein Structure, Tertiary; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases/genetics; Protein Tyrosine Phosphatases/metabolism; Proto-Oncogene Proteins/metabolism; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; SH2 Domain-Containing Protein Tyrosine Phosphatases; Signal Transduction/physiology; Transcription Factors; Vault Ribonucleoprotein Particles/genetics; Vault Ribonucleoprotein Particles/metabolism; ets-Domain Protein Elk-1

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MK01

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14764

F

Seeded From UniProt

complete

HUMAN:PTN11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14764

F

Seeded From UniProt

complete

HUMAN:PTN11

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

HUMAN:PTN11

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

HUMAN:PTN11

involved_in

GO:0035335: peptidyl-tyrosine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q14764)
  • happens_during:(GO:0070849)
  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:MVP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q06124

F

Seeded From UniProt

complete

HUMAN:MVP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P28482

F

Seeded From UniProt

complete

HUMAN:MVP

enables

GO:0019903: protein phosphatase binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002327)

Seeded From UniProt

complete

HUMAN:MVP

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000057)

Seeded From UniProt

complete

HUMAN:MVP

involved_in

GO:0038127: ERBB signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MVP

involved_in

GO:0008283: cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:MVP

involved_in

GO:0072376: protein activation cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_output:(UniProtKB:P41969)

Seeded From UniProt

complete

HUMAN:MK01

involved_in

GO:0038127: ERBB signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTN11

involved_in

GO:0038127: ERBB signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTN11

involved_in

GO:0035335: peptidyl-tyrosine dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_direct_input:(UniProtKB:Q14764)
  • happens_during:(GO:0070849)
  • occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:PTN11

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

HUMAN:PTN11

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0000057)

Seeded From UniProt

complete

HUMAN:PTN11

enables

GO:0004725: protein tyrosine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PTN11

enables

GO:0004721: phosphoprotein phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

See also

References

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